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Review
. 2023 Oct 13;15(1):175.
doi: 10.1186/s13195-023-01314-6.

Biomarkers in Alzheimer's disease: role in early and differential diagnosis and recognition of atypical variants

Bruno Dubois #  1   2 , Christine A F von Arnim #  3 , Nerida Burnie  4   5 , Sasha Bozeat  6 , Jeffrey Cummings  7
Affiliations
Review

Biomarkers in Alzheimer's disease: role in early and differential diagnosis and recognition of atypical variants

Bruno Dubois et al. Alzheimers Res Ther. .

Abstract

Background: Development of in vivo biomarkers has shifted the diagnosis of Alzheimer's disease (AD) from the later dementia stages of disease towards the earlier stages and has introduced the potential for pre-symptomatic diagnosis. The International Working Group recommends that AD diagnosis is restricted in the clinical setting to people with specific AD phenotypes and supportive biomarker findings.

Main body: In this review, we discuss the phenotypic presentation and use of biomarkers for the early diagnosis of typical and atypical AD and describe how this can support clinical decision making, benefit patient communication, and improve the patient journey. Early diagnosis is essential to optimize the benefits of available and emerging treatments. As atypical presentations of AD often mimic other dementias, differential diagnosis can be challenging and can be facilitated using AD biomarkers. However, AD biomarkers alone are not sufficient to confidently diagnose AD or predict disease progression and should be supplementary to clinical assessment to help inform the diagnosis of AD.

Conclusions: Use of AD biomarkers with incorporation of atypical AD phenotypes into diagnostic criteria will allow earlier diagnosis of patients with atypical clinical presentations that otherwise would have been misdiagnosed and treated inappropriately. Early diagnosis is essential to guide informed discussion, appropriate care and support, and individualized treatment. It is hoped that disease-modifying treatments will impact the underlying AD pathology; thus, determining the patient's AD phenotype will be a critical factor in guiding the therapeutic approach and the assessment of the effects of interventions.

Keywords: Alzheimer’s disease; Biomarkers; Blood-based biomarkers; Cerebrospinal fluid; Diagnosis; Magnetic resonance imaging; Mild cognitive impairment; Phenotype; Positron emission tomography; Prodromal stage.

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Conflict of interest statement

B.D. is a consultant for ABScience, Biogen, Eli Lilly, MedAvante, and Qynapse, and has received research grants for his institution from AVID, Fondation Merck-Avenir, Fondation de Recherche sur Alzheimer (FRA), Pfizer, and Roche. C.A.F.v.A. has received: honoraria for serving on the scientific advisory board of Biogen, Dr. Willmar Schwabe GmbH & Co. KG, Novo Nordisk, and Roche; funding for travel and speaker honoraria from Biogen, Dr. Willmar Schwabe GmbH & Co. KG, Medical Tribune Verlagsgesellschaft mbH, Novartis, and Roche Diagnostics AG; and research support from Roche Diagnostics AG. N.B. has no competing interests to declare. S.B. is a full-time employee of F. Hoffmann-La Roche AG. J.C. has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Biogen, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lilly, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Signant Health, Suven, and United Neuroscience pharmaceutical, assessment, and investment companies. J.C. is supported by: the Alzheimer’s Disease Drug Discovery Foundation (ADDF); the Joy Chambers-Grundy Endowment; NIA grant P20AG068053; NIA grant R01AG053798; NIA grant R35AG71476; NIGMS grant P20GM109025; NINDS grant U01NS093334; and Ted and Maria Quirk Endowment for the Pam Quirk Brain Health, and Biomarker Laboratory.

Figures

Fig. 1
Fig. 1
Prevalence of typical and atypical clinical phenotypes of AD in a clinical samplea aThe clinical sample comprised 523 patients who were consecutively referred to a specialist dementia clinic and diagnosed with AD; 42 patients had MCI and are not included in the pie chart [12]. Patients with language presentation most likely had lvPPA, though it is possible patients may have had nfPPA. AD, Alzheimer’s disease; CBS, corticobasal syndrome; lvPPA, logopenic variant of primary progressive aphasia; MCI, mild cognitive impairment; nfPPA, non-fluent primary progressive aphasia; PCA, posterior cortical atrophy; svPPA, semantic variant primary progressive aphasia
Fig. 2
Fig. 2
Summary of anticipated biomarker results for the different clinical phenotypes of AD. Decreased plasma Aβ42/40 ratio is extended across all clinical phenotypes, as there is evidence of increased Aβ plaques across the phenotypes. Decreased plasma Aβ42/40 ratio has been identified across the AD continuum [26, 28]; however, further studies are warranted to investigate the utility of the Aβ42/40 ratio across the clinical phenotypes. Aβ, amyloid-beta; Aβ42/40 Aβ (1–42)/(1–40); AD, Alzheimer’s disease; BBBM, blood-based biomarker; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose; FTD, frontotemporal dementia; MRI, magnetic resonance imaging; PET, positron emission tomography; pTau, phosphorylated tau; tTau, total tau
Fig. 3
Fig. 3
FDG-PET across the clinical phenotypes of AD: A typical AD, B PCA, and C lvPPA. Panel A shows symmetrical bilateral parietal and temporal hypometabolism in a patient with typical AD. Panel B shows bilateral reduction in parieto-tempo-occipital metabolism in a patient with PCA. Panel C shows greater hypometabolism in the left parieto-temporal region compared with the right parieto-temporal region in a patient with lvPPA. Panels 1 and 2 show different depths within the brain. The FDG-PET images in Fig. 3 are courtesy of Dr. Marie-Odile Habert (Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, APHP, Paris). AD, Alzheimer’s disease; FDG, fluorodeoxyglucose; lvPPA, logopenic variant of primary progressive aphasia; PCA, posterior cortical atrophy; PET, positron emission tomography
Fig. 4
Fig. 4
The role of AD biomarkers in the clinical setting. AD, Alzheimer’s disease; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; NfL, neurofilament light chain; PET, positron emission tomography
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